Cellular encapsulation has been a subject of research for several decades as a means to mask transplanted cells from the in vivo host. By coating the cells with a highly biocompatible layer, surface antigens, inflammatory proteins, and other agents that may instigate an immune/inflammatory response may be dampened or eliminated. In order to develop a reasonable method to encapsulate a cell, the process must not be detrimental to the cells and result in a highly biostable and biocompatible coating. Cellular encapsulation through the use of highly purified alginate has shown significant promise. In fact, clinical trials using islets within alginate capsules in the absence of an immunosuppression regimen are ongoing worldwide. However, to date, studies using this approach have failed because 1) the resulting gels are unstable; and 2) the resulting coating prevents adequate nutrient delivery for highly metabolically active cells, such as islets of Langerhans.
Various permutations of alginate and/or PEG encapsulation of mammalian cells has been patented, including U.S. Pat. Nos. 4,353,888; 4,673,566; 4,689,293; 4,806,355; 4,923,645; 5,762,959 and 5,766,907). However, most of these methods produce alginate gels that degrade over time due to leakage of divalent cations.
Additional research has been conducted to attempt to increase the stability of alginate and/or PEG-based gels through the use of covalent cross-linking. For example, free radical polymerization generation of capsules to entrap mammalian cells has been disclosed in U.S. Pat. Nos. 5,334,640; 5,410,016; 5,700,848; 5,705,270; and 6,258,870. However, these techniques have not proven useful because these methods induce moderate to severe cell damage, particularly for cells that are vulnerable to oxidative stress, such as islets of Langerhans.
Layer-by-layer coating of thin films has multiple biomedical applications, from enhancing biocompatibility of an inert implant, to immune-camouflage of a cellular transplant, to local drug delivery.
Layer-by-layer encapsulation has been used for temporal drug delivery for multiple applications. Drug microcrystals, proteins, or enzymes can be encapsulated and the rate of release can be modified through the properties of the coating and their subsequent thickness. Furthermore, the overall polymer load is substantially reduced, given that the thickness of the coating can be intricately controlled. Agents may be encapsulated in their crystalline form, or via infiltration into a matrix that is subsequently coated. Of note, recent published applications of layer-by-layer methods for drug delivery include: ibuprofen, furosemide, doxorubicin, rifampicin, curcumin, or even peptides or enzymes.